LOW GRADE GLIOMA controversies in management

1. LOW GRADE GLIOMAS:
MANAGEMENT
CONTROVERSIES
DR PRAVEEN K
TRIPATHI
29-Mar-17
1

2. OVERVIEW
 Gliomas are the most common primary brain neoplasms in
adults.
 The term low-grade glioma (LGG) refers to tumors
classified by the World Health Organization (WHO) as
grades I and II, including oligodendrogliomas,
astrocytomas, and mixed oligoastrocytomas.
 While the 2007 WHO classification of gliomas was based
on histological subtype (astrocytic, oligodendrocytic, and
oligoastrocytic), the 2016 classification groups together
astrocytic and oligodendroglial tumours and further
defines specific entities based on IDH mutation and
1p/19q codeletion status
29-Mar-17
2

3. OVERVIEW
 LGGs have a better prognosis than their anaplastic
counterparts; the 10-year overall survival rate for patients with
WHO grade II astrocytomas is 35%.
 LGGs have the potential to dedifferentiate into high-grade
tumors, and approximately 50% to 75% of WHO grade II
gliomas transform within 6 to 7 years of diagnosis.
 LGGs are primarily reported in the frontal lobes (44%),
followed by the temporal (28%) and parietal (14%) domains.
 Interestingly, LGGs originating in the cerebellar region are
associated with a better prognosis than those originating
supratentorially.
29-Mar-17
3

4. OVERVIEW
 The mean age at diagnosis is 39.4 years
 Factors associated with longer survival time are
 Younger age,
 Caucasian race,
 Tumor histology, and
 Extent of resection.
 The most common histologic subtype of LGG is astrocytoma
(69.3%), followed by oligodendroglioma (21.1%) and mixed
glioma (9.6%).
 Factors associated with an increased risk of glioma
 Exposure to highdose radiation,
 Increasing age, and
 Hereditary disorders such as li-fraumeni syndrome and neurofibromatosis
type 1
29-Mar-17
4

5. Clinical Presentation
 Epilepsy(65%-95%)
 Headache(40%)
 Normal neurological examination
 Focal neurological deficits
 Papilloedema
 Neuro-endocrine disturbance
The most common initial clinical presentation of patients with
LGGs is seizures, followed by headaches.
Symptoms from tumor mass effect are comparatively less
common, probably owing to a slow growth rate (on average,
4.1 mm/yr)
29-Mar-17
5

6. MANAGEMENT-CONTROVERSIES
 The treatment of low-grade gliomas remains one of the
most uncertain and controversial areas of modern
neurosurgery.
WHY CONTROVERSIES
 The controversy largely stems from the lack of well-
designed clinical trials with adequate follow-up to account
for the relatively long progression-free survival and
overall survival of patients with LGG.
 No evidence of class I or II exists regarding the optimal
management of these patients
29-Mar-17
6

7. WHAT CONTROVERSIES
1. Standard antiepileptic drug regimen for seizure control.
2. What neuroradiological features should guide management?
3. Which prognostic factors can help discriminate between favourable
and unfavourable patients with LGG?
4. Based on molecular characterization of tumours are there subgroups
of patients that benefit from more aggressive treatment modalities?
5. Should observation or surgery?
6. At what time should it be interveined? What surgery
7. What is the impact of extent of resection on PFS and OS in patients
with LGG?
8. What is the role of RT in the management of patients with LGG?
9. What is the role of chemotherapy in the management of LGG?
10. What protcol in follow up?
11. How should patients with recurrence be managed?
29-Mar-17
7

8. Standard antiepileptic drug regimen
 There is no standard antiepileptic drug regimen for seizure control
in patients with tumors; however, levetiracetam is preferentially
used because of its favorable pharmacologic properties and
relatively benign side-effect profile.
Yuan Y, Yunhe M, Xiang W, et al. P450 enzyme-inducing and non enzymeinducing
antiepileptic drugs for seizure prophylaxis after glioma resection surgery: A meta-analysis.
Seizure. 2014;23:616–621.
 There is no level I evidence that levetiracetam is more effective
than phenytoin for seizure control.
 Unlike phenytoin, levetiracetam does not induce hepatic
cytochrome P450 enzymes; therefore, levetiracetam has a lower
risk of potential adverse interactions with adjuvant chemotherapy
treatments.
 Starting dosages for levetiracetam range from 1000 to 4000
mg/day; dosages as high as 5000 mg/day are also well tolerated by
patients with intractable seizures
29-Mar-17
8

9. Diagnostic Neuroimaging for LGG
 Magnetic resonance imaging (MRI) of LGGs demonstrates
lesions that are isointense/hypointense on T1-weighted images,
are homogeneously hyperintense on T2-weighted images, and
do not enhance with contrast administration .
 Calcifications can be detected in about 20% of lesions and
appear as distinct hyperintense foci on T1-weighted images and
hypointense foci on T2-weighted images.
 Vasogenic edema and necrosis are not typical of LGGs, owing
to their slow growth rate.
 MR spectroscopy, have been used to differentiate glioma grades
and even to detect key LGG metabolic mutations, such as those
of the isocitrate dehydrogenase 1 (IDH1) gene
29-Mar-17
9

10. Diagnostic Neuroimaging for LGG
A 32-year-old woman presenting with partial motor seizures. (A and E) The MRI reveals
a right frontal mass which is hypointense on T1-weighted images, (B and F) Does not enhance
following administration of contrast, (C and G) The lesion expands the cortex locally and has a
sharp border with minimal surrounding vasogenic edema as seen on T2, (D and H) FLAIR images
29-Mar-17
10

11. Diagnostic Neuroimaging for LGG
 Both fluorodeoxyglucose-PET (FDG-PET) and
fluorothymidine-PET (FLT-PET) have been used to evaluate
LGG metabolism and proliferation.
 A prospective study of 60 patients with cerebral gliomas
evaluated the ability of FDG-PET to differentiate LGGs from
HGGs. The investigators reported a PPV of 97.3% and an NPV
of 70.2%.
Watanabe M, Tanaka R, Takeda N. Magnetic resonance imaging and histopathology of
cerebral gliomas. Neuroradiology. 1992;34:463–469.
 Similarly, diffusion tensor imaging (DTI) is under investigation
to differentiate low-grade and high-grade histologic
appearances.
 DTI analysis of 79 gliomas also demonstrated a correlation
with the tumor grade and was able to differentiate LGGs from
HGGs with a sensitivity of 92% to 94% and a specificity of
53% to 54%.
29-Mar-17
11

12. Diagnostic Neuroimaging for LGG
29-Mar-17
12
Diffusion tensor imaging and tractography can often help to identify location of
fiber tracts in relation to tumors and to demonstrate whether these white matter
bundles are displaced or invaded by infiltrating tumor cells

13. Diagnostic Neuroimaging for LGG
29-Mar-17
13
Diffusion tensor imaging (DTI) and tractography can provide an elegant visualization of the
white matter tracts and their relationship with infiltrating tumors.
In this example, the right corticospinal tract (motor fibers from the foot area) is
displaced medially rather than being invaded by the tumor. The DTI and tractography
can often help to maximize surgical resection while preserving neurological function

14. Diagnostic Neuroimaging for LGG
 fMRI is an activation-based method that identifies all regions
of the brain that demonstrate activity related to a particular
task, regardless of whether those areas are essential or
supplementary.
 Consequently, areas that appear negative for language when
cortical stimulation is used may still demonstrate fMRI
activation, producing false-positive results.
 Decreased specificity may also be expected because fMRI is a
perfusion-based method and does not directly detect neuronal
activity.
 Magnetoencephalography (MEG) is also increasingly used for
preoperative functional mapping. MEG imaging reconstructs
the spatiotemporal dynamics of brain sources from
magnetoencephalographic data.
29-Mar-17
14

15. Diagnostic Neuroimaging for LGG
29-Mar-17
15
Functional MRI -the left hand motor area can be effectively localized in relation to the
right posterior frontal tumor involving the motor strip

16. Prognostic Factors, Patient Outcome, and
Survival
 University of California at San Francisco (UCSF) conducted a
retrospective study of 256 patients and proposed a scoring
system to estimate patient overall survival (OS) and
progression-free survival (PFS).
 This scoring system assigns a 1-point value for the following
factors:
 Tumor location within eloquent cortices,
 Karnofsky performance scale score 80 or less,
 Age more than 50 years, and
 Maximal tumor diameter more than 4 cm.
 Higher scores portend a worse prognosis.
 Patients with a UCSF score of 0 to 1 had a 97% 5-year
survival rate, and patients with a score of 3 to 4 had a 5-year
survival rate of 56% 29-Mar-17
16

17. Prognostic Factors, Patient Outcome, and
Survival
Prognostic factors for survival in adult patients with cerebral low-grade glioma.
Pignatti F, van den Bent M, Curran D etal 2002
29-Mar-17
17

18. Prognostic Factors, Patient Outcome, and
Survival
 Radiation Therapy Oncology Group, and the North Center
Cancer Treatment Group (RTOG/NCCTG) further defined
prognostic factors for WHO grade II gliomas.
 PFS and OS were negatively affected by the following
factors:
 Impaired baseline neurologic status,
 Shorter time since first symptoms (<30 weeks),
 Astrocytic histology, and
 Maximal tumor diameter greater than 5 cm.
 Early radiation therapy was correlated with improved PFS
but had no impact on OS.
29-Mar-17
18

19. LGG: Molecular Markers
 Specific genetic markers helpful in dividing gliomas into subgroups
with respect to prognosis and response to chemotherapy
 TP53 mutations: Common in diffuse astrocytomas and are
mutually exclusive from 1p/19q co-deletions.
 1p/19q Deletions: 50-70% LG Oligodendroglial tumors
 Loss of 1p or both 1p/19q may predict chemosensitivity and predicts
prolonged survival in LGO and LGOA
 There are patients that are deleted that do less well than most and there
are some intact patients that do much better than most.
 IDH 1 mutations: 60-90% of LGG. Associated with improved
survival.
 May help diagnostically differentiate: gliosis vs tumor or (in comb w
BRAF) pilocytic tumors vs grade II astrocytoma
 We still do not know confidently if IDH 1 mutations should be used to
direct treatment or, if so, how.
29-Mar-17
19

20. LGG: Treatment
 Symptom Management
 Observation
 Surgery
 Radiation Therapy
 Chemotherapy
How to intervene
To intervene or not
When to intervene
Surgery ; Radical Vs Partial
Radiotherapy: Timing,
Low Vs High Dose
Role of Chemotherapy
29-Mar-17
20

21. LGG: Symptom Management
•Seizures: Medications such as levitiracetam, lacosamide,
topirimate, lamotrigine, and others such as phenytoin,
carbamazepine, etc
•Edema: Steroids, usually dexamethasone; however long
term use has potential for side effects (skin changes,
weight gain, muscle weakness, bone thinning, increased
risk of infection, etc)
•Obstructive Hydrocephalus: may require surgery and
perhaps placement of a “shunt” to bypass the blockage and
lower the pressure
29-Mar-17
21

22. “Watchful waiting” WHY
 Characteristic imaging features with long history.
 Increased life span by surgery never proven.
 Increasingly patients are diagnosed neurologically intact.
 Postpones surgical morbidity and mortality if any.
 Alternate treatment strategy are available
 Stereotactic biopsy and radiotherapy
 Technical reasons
 Distinction between tumor-brain difficult and early radical surgery
seldom serves purpose.
29-Mar-17
22

23. “Watchful waiting” - WHY NOT
 Grading gliomas based on imaging characteristics alone underestimated the degree
of malignancy in 1/3 cases
 Tissue diagnosis should be attained whenever deemed safe and possible
Scott JN, Brasher PM, SevickRu, Rewcastle NB, Forsyth PA. How often are nonenhancingsupratentoralgliomas malignant?
A popultion study. Neurology 2002:s9:947-9.
 Recent studies have showed that contrast enhancement may occur in upto 40% of
low grade gliomas.
 Scott CB, Scarantino C, Urtasun R, Movsas B, Jones CU, Simpson JR, eta. validation and predictive power of Radiation
Therapy Oncology Group (RTOG) recursive partitioning analysis classes ror malignant glioma patients: A report using
RTOG 90-06. Int J RadiatOncolBiol Phys 1998;40:51-5.
 The expectant management of patients with LGGs can bring on other risks, such as,
 Malignant degeneration
 Subsequent tumorgrowth, and
 Irreversible neurological deficit.
 How ever despite these theoretical risks, several retrospective series revealed that
the timing of surgical intervention did not affect the rates of malignant
transformation, overall survival, or QOL.
 Reijneveld JC, Sitskoorn MM, Klein M, Nuyen J, Taphoorn Mj. Cognitive status and quality of life in patients with
suspected versus proven low grade gliomas, Neorology 2001;56:618-23 29-Mar-17
23

24. Surgery
 The role of immediate surgical resection versus delayed
resection is controversial and data are limited to observational
studies.
 Unless contraindicated, immediate surgical resection is an option
over observation to improve OS.
 Although no randomized controlled trials (RCTs) have evaluated
the extent of surgery on outcomes in LGG, numerous
observational studies suggest that greater extent of resection
(EOR) improves OS and seizure control.
 Maximizing tumour resection while keeping the surgically
induced deficit at an acceptable level is recommended over
simple debulking.
 Surgery alone is not curative in patients with LGG and
additional therapy with RT and/or chemotherapy will likely be
required at some point in their disease trajectory.
29-Mar-17
24

25. The pros and cons of resection of gliomas
29-Mar-17
25

26. Surgery – WHEN
RATIONALE FOR EARLY SURGERY
 Definitive diagnosis
 Possibility of gross total resection with potential for cure
 Control of seizures
 Neurological improvement
 Control of ICP
 Longer disease free interval
 Enhanced ability of immune cells to wipe out tumor
 Greater kill by post op RT
DISAGREEMENT WITH EARLY SURGERY
 Longer disease free interval is lead time bias
 Immunological activity against low grade glioma is controversial
 Post op radiotherapy does not kill all cells
29-Mar-17
26

27. Surgery –WHAT
Stereotactic Biopsy
 Operative strategies for patients with LGGs include open surgical
resection and stereotactic biopsy.
 The choice depends in part on the patient's clinical status, the
anatomic location of the tumor, and the surgeon's preference.
 Immediate stereotactic biopsy is increasingly uncommon, it remains
a reliable first step for cases in which the diagnosis is uncertain.
 A recent Norwegian study had shown the significant difference of
survival in those centers with a preference for resection than those
selecting a biopsy and watchful waiting and with no significant
difference in health related quality of life
Jakola AS, Myrmel KS, Kloster R, Torp SH, Lindal S, Unsgard G, Solheim O (2012)
Comparison of a strategy favoring early surgical resection vs a strategy favoring
watchful waiting in low-grade gliomas. JAMA 308:1881–1888
29-Mar-17
27

28. Surgery –WHAT
Microsurgical Resection
 In patients with accessible LGGs who have symptoms of local
mass effect, increased intracranial pressure, and intractable
seizures, the role of microsurgical resection is well established.
 Resection serves several purposes in these circumstances,
including alleviation of mass effect, cytoreduction, and
diagnosis.
 Cytoreduction can also reduce cerebral edema and potentially
improve radiosensitivity and chemosensitivity of the tumor.
 The degree of tumor removal afforded by open surgical
resection also offers the advantage of providing more tissue for
histologic analysis.
29-Mar-17
28

29. Surgery –WHAT
EXTENT OF RESECTION
 Till date no class 1 evidence to support radical resection.
 There are lot of retrospective data to suggest benefit in survival and
in quality of life.
 Two prospective studies have shown benefit of extensive surgery in
overall survival on univariate analysis.
 On multivariate analysis these showed minimal benefits.
 Recent studies looking specifically at oligodendroglioma show that
extent of resection does improve PFS and overall survival but did
not influence time to malignant transformation.
Snyder LA, Wolf AB, Oppenlander ME, Bina R, Wilson JR, Ashby L, Brachman
D, Coons SW, Spetzler RF, Sanai N (2013) The impact of extent of resection on
malignant transformation of pure oligodendrogliomas. J Neurosurg.
doi:10.3171/2013.10. JNS13368 29-Mar-17
29

30. Surgery –WHAT
EXTENT OF RESECTION
 Hardesty and Sanai reviewed every major peer-reviewed clinical
publication on the role of EOR in glioma outcome between the years
1990 to 2012.
 Eleven LGG articles were examined for quality of evidence,
expected EOR, and survival benefit.
 Three studies using volumetric analysis to determine EOR in LGG
pts (n=462, range 90-216) demonstrated a benefit to increasing EOR
in univariate and/or multivariate analysis.
 Five-year OS was improved in all studies
Hardesty DA, Sanai N. The value of glioma extent of resection in the
modern neurosurgical era. Front Neurol 2012 Oct 18;3:140
29-Mar-17
30

31. 29-Mar-1731

32. Surgery –WHAT
Contemporary neurosurgical methods
 Contemporary neurosurgical methods, including ultrasonography,
functional mapping, frameless navigational resection devices, and
intraoperative imaging techniques, enable the neurosurgeon to
achieve more extensive resections with less morbidity.
 Intraoperative ultrasonography provides real-time intraoperative
data and is helpful in detecting the tumor, delineating its margins,
and differentiating tumor from peritumoral edema, cyst, necrosis,
and adjacent normal brain tissue.
 Intraoperative MRI may also allow for greater extent of resection,
particularly when tumor-infiltrated tissue cannot be grossly
distinguished from normal.
Claus EB, Horlacher A, Hsu L, et al. Survival rates in patients with low-grade
glioma after intraoperative magnetic resonance image guidance. Cancer.
2005;103:1227–1233. 29-Mar-17
32

33. Surgery –WHAT
Contemporary neurosurgical methods
 Stimulation mapping techniques are essential to minimize morbidity
and to achieve radical resections of tumors located in or around
cortical and subcortical, functionally eloquent sites.
 Intraoperative mapping techniques can effectively identify tissue
with motor, language, and sensory functionality.
Sanai N, Berger MS. Intraoperative stimulation techniques for functional pathway
preservation and glioma resection. Neurosurg Focus. 2010;28
 Awake language mapping is also essential owing to variability in the
localization of language pathways and should be considered when a
glioma is located in the dominant hemisphere near the frontal
operculum, temporal lobe, or angular gyrus.
 Caution should be observed during resection owing to the
possibility that functional brain tissue resides within the tumor itself.
29-Mar-17
33

34. Surgery –WHAT
Functional Mapping and Cortical Stimulation
29-Mar-17
34

35. 29-Mar-17
35
A 43-year-old man presenting with word finding difficulties. He underwent an awake
craniotomy for aggressive resection of the tumor involving Wernicke’s area with language
and motor cortex mapping. Note the multicompartmental endopial resection of the tumor
with preservation of the cortical veins overlying the tumor

36. Defer Treatment Treat
 Suspicion: ? Higher grade
 Progressing LG
 Enhancement
 Mass effect
 Symptomatic
 > age 40
 Surgery not indicated or
significant residual and Rx
necessary
Post op: When Should We Treat?
 After large or GTR
 Minimal disease
 No enhancement
 Seizures controlled
 Few or no Seizures
 Younger age
29-Mar-17
36

37. Radiation Therapy
 Became a cornerstone of therapy many yrs ago
 Oligodendrogliomas, Astroctomas, Mixed OA all respond
 Proton beam thought to decrease risk to normal brain
however efficacy has not been compared to standard
external beam with margins. Risk is under treating the
margins
 Stereotactic: Not usually indicated. Focused to small area,
but these tumors are infiltrative and “spread out”
 RT may not always be best initial choice: Chemotherapy
may be the 1stchoice for some pts, particularly with
Oligodendrogliomaor Mixed OA whose tumors show 1p/19q
deletions–deferring treatment with RT
29-Mar-17
37

38. Why/why not Radiation?
Why radiation therapy?
 Improves time to tumor progression
 Several studies show improved survival in patients with
progressing or aggressive tumors
 No systemic side effects
 Defined treatment time
Why not radiation therapy?
 No clear evidence of improved survival with immediate post op
RT vs delayed RT
 Delayed radiation induced neurotoxicity
 RT vs no RT
 Perform worse on cognitive tests
 Have lower Karnofskyscore
 Not accounted for by histology, location, extent of removal, progression
• Surm-aho et al, 2001
29-Mar-17
38

39. Why/why not Radiation?
RT of benefit
 –Gannett et al, 1994
 –Wallneret al, 1988
 –Morket al, 1985
RT of no benefit
 –Shaw et al, 1992
 –Bullard et al, 1997
 –Nijjaret al, 1993
RT of benefit in some, but not all
 Morket al, 1985: not in pts with GTR
 Celli et al, 1994: not in pts with
indolent tumors;
29-Mar-17
39

40. Why/why not Radiation?
 In the Mayo Clinic study, Shaw et al compared the
outcome of 126 patients with supratentorial astrocytoma
or mixed oligo-astrocytoma treated with surgery alone or
surgery plus either low-dose (53 Gy) or high-dose (53
Gy) RT.
 The 5-year OS was 32% with surgery alone, 47% with
low-dose RT, and 68% with high-dose RT, suggesting that
surgery without postoperative RT was inadequate
treatment and high-dose RT was better than lower dose.
Shaw EG, Daumas-Duport C, Scheithauer BW, et al: Radiation therapy in the
management of low-grade supratentorial astrocytomas. J Neurosurg 70:853-
61, 1989
29-Mar-17
40

41. Immediate vs delayed PORT
29-Mar-17
41
Evidence
Phase III adult low grade glioma trials (EORTC 22844 and
22845): Risk Factors identified & Validated
Age>40 years
Size>6cm
Crossing Midline
Pure Astrocytoma histology
Neurological deficit before Surgery
Low Risk Patient: </= 2 factors (Median Survival- 7.7 years)
High Risk: 3 or more factors (Median Survival- 3.2 years)

42. Immediate vs delayed PORT
29-Mar-17
42
EORTC 22845 (Karim et al, 2002 & Van den Bent et al,
2005)
Randomised phase III trial
RT Dose (54Gy/30#)
Immediate RT vs RT at Progression
Results: Improved median progression free survival
(5.3 yrs vs 3.4 yrs)
Better seizure control rates
No difference in Median survival (7.4yrs vs 7.2 yrs)
No difference in rate of malignant transformation.
Pitfall: No in-depth quality of life adjusted analysis.

43. Immediate vs delayed PORT
29-Mar-17
43
RTOG (Radiation Therapy Oncology Group) 9802 (phase
II portion of protocol)
Risk Factors predictive of a poorer PFS
Astrocytoma histology
Residual tumor of >/=1 cm on Postop MR
Pre-operative tumor diameter of >/=4 cm
Patients with:
All three unfavourable factors- PFS at 5years 13%
None of the three factors- PFS at 5years 70%

44. Why/why not Radiation?
Delayed Radiation Encephalopathy
29-Mar-17
44

45. So, on the basis of discussed data
Observation seems to be a reasonable strategy for the most
favorable subset i.e.
<1 cm residual tumor
Preoperative tumor diameter <4 cm
Oligodendroglioma histology
Younger patients
Following a gross total resection (GTR).
Mature result of this trial is pending !!!!
Radiation Therapy-Standard approach
29-Mar-17
45

46. Radiation Therapy-Standard approach
2] Dose of RT?
Evidence
EORTC 22844 (Karim et al. 1996) – phase III:
Postoperative RT 45 Gy vs. 59.4 Gy
5-year OS 58% with 45 Gy
59% with 59.4 Gy.
INT/NCCTG (Shaw et al. 2002) – phase III:
Postoperative RT 50.4 Gy vs. 64.8 Gy
5-year OS 73% with 50.4 Gy
68% with 64.8 Gy.
29-Mar-17
46

47. Based on these Phase III trials and Extrapolation of data of
in-field recurrences in high grade gliomas
It will be prudent to limit the Postoperative
RT Dose to 54 Gy.
29-Mar-1747

48. Why/Why Not Chemotherapy?
Why Chemotherapy?
 Spares the normal tissue of the brain the delayed effect of RT
 Some low grade glioma sare quite large meaning larger
radiation ports resulting in larger areas of normal brain exposed
to RT
 Some low grade gliomas; particularly ones with 1p/19q
deletions are particularly sensitive
Why not Chemotherapy?
 Responses disappointing in some low grade gliomas;
particularly those without 1p or 1p/19q deletions
 Prolonged treatment
 Systemic (body) toxicity
 Quality of life over time
29-Mar-17
48

49. RT Alone or RT + Chemotherapy?
29-Mar-17
49
Evidence
INT/RTOG 9802 trial
(ASCO abstract 2008): phase III
Low-risk (<40 year + GTR) observed until symptoms
High-risk (>40 year or STR or biopsy) patients randomized to
RT alone vs. RT --> PCV ×6 cycles q8 weeks
5 year OS was 72 vs. 63% (p = 0.33)
5-year PFS was 63 vs. 46%
(p = 0.06) in favour of chemotherapy

50. RT Alone or RT + Chemotherapy?
29-Mar-17
50
Largest reported retrospective analysis of 149 patients
Temozolomide at Progression (1p/19q LOH was present in
42%)
53% - Objective response (15% - Partial response and 38%
minor response)
37% - Stable disease
10% - progressive disease.
Kaloshi G, Benuaich-Amiel A, Diakite F, et al: Temozolomide for low grade
gliomas: predictive impact of 1p/19q loss on response and
outcome. Neurology 2007; 68:1831-1836

51. 29-Mar-17
51
 Phase II Trial of Temozolomide in Patients With
Progressive Low-Grade Glioma
(Jennifer A. Quinn et al)
Objective response rate - 61% (24% CR and 37% PR)
Stable disease - 35%
IDH1 or IDH2 mutations predict longer survival and
response to temozolomide in low-grade gliomas.
(C. Houillier et al) Neurology October 26, 2010 vol. 75 no. 17 1560-1566
1p-19q codeletion, MGMT promoter methylation, and IDH mutation (p = 0.01)
were correlated with a higher rate of response to temozolomide

52. 29-Mar-17
52
 EORTC 22033-26033/CE5 phase III randomized trial for low
grade glioma: Phase III EORTC 22033-26033/NCIC CE5
intergroup trial compares 50.4 Gy radiotherapy with up-front
temozolomide in previously untreated low-grade glioma (Open to
accrual)
Conclusion:
 Low-grade gliomas respond to temozolomide
 Loss of chromosome 1p/19q predicts both a durable
chemosensitivity and a favorable outcome

53. If Chemotherapy added to RT- Which
Chemotherapy?
29-Mar-17
53
 Concerns about toxicity profile of PCV
 Nitrosoureas (In PCV) – Notorious for secondary malignancy
 Procarbazine - Infertility
 Availability of lesser toxic and effective substitute as
Temozolomide
 Oral administration- Convenient dosing of Temozolomide
Makes Temozolomide more preferable an option with respect
to PCV chemotherapy

54. Disease Progression after PORT?
29-Mar-17
54
Options Include
Resurgery (If resectable)
Chemotherapy (Unresectable disease)
Reirradiation with SRS/FSRT (Small recurrences)
Newer agents under trial (Blocking mTOR with an
investigational agent ridaforolimus ).

55. Chemotherapy
 Many/most low grade Oligodendrogliomas respond to
chemotherapy; sometimes dramatically and for prolonged
periods
 Clinical improvement, decreased szeven in patients without
obvious improvement on MRI
 PCV (procarbazine, CCNU, vincristine)
 Temozolomide
 Length of treatment? Clearer with PCV than TMZ but PCV more
toxic
 1p/19q loss predicts response-in almost all pts
 Pts with 1p/19q intact LGO, LGOA, LGA less likely to respond
to chemotherapy; may be better served by RT if/when they need
treatment
29-Mar-17
55

56. Chemotherapy
Chemotherapy Risks/Toxicity
 Myelosuppression: acute, chronic, delayed
 Other organ toxicities
 Quality of life
 Toxicity of PCV significant and dose limiting
 Temozolomide
 significantly less toxic
 Length of treatment & response rate need to be defined
29-Mar-17
56

57. Temozolomide
 Classification = alkylating agent
 Rapid conversion at physiologic pH to MTIC (, CSF
concentration is 30% of serum
 MTIC cytotoxicity due to methylation of DNA at the O6
position of guanine
 Antitumor activity is schedule dependent
 Cytotoxicity influenced by levels of MGMT
 Levels not infuenced by cytochrome p450
 Renal and hepatic clearance minor
29-Mar-17
57

58. Temolozomide Toxicites
 DLT is myelosuppression, nadir 21-28 days, recovery
within 14 days of nadir
 Immunosuppression (lymphopenia)
 Nausea and vomiting
 Infertility and mutagenesis
29-Mar-17
58

59. Chemotherapy
Oligodendroglioma1p/19q deleted 6 cycles of Temozolomide
29-Mar-17
59

60. Targeted Therapy
 Glioma cells express receptors for several different growth
factors
 PDGF, VEGF, EGF
 Targeted therapies aim to inhibit these growth factor
receptors and their tyrosine kinasebased intracellular
signaling pathways
 Agents bind to cell surface receptors and either compete w/
or block the normal substrates from binding or bind directly
to the growth factor
 In tumors dependent on such pathways for growth, the use
of these agents can potentially result in tumor cell death
29-Mar-17
60

61. 29-Mar-1761

62. Therapeutic strategy for LGG stratified by EOR,
histological subtype, and molecular status
29-Mar-17
62
Nitta et al: Neurol Med Chir (Tokyo) 53:447–454, 2013

63. Conclusion
 Innovations within the diagnostic, therapeutic, and molecular domains are
intertwining and helping to understand and treat LGGs more effectively.
 Prognostic factors derived from genetic analysis and clinical
characteristics allow us to stratify patients into proper treatment groups to
maximize therapeutic benefit.
 Maximizing the extent of resection can delay recurrence and improve the
time to transformation.
 However, this approach must be balanced with preservation of neurologic
function, which can be improved by using intraoperative mapping.
 Chemotherapy combined with radiation therapy may prolong PFS and OS.
 LGGs are not homogeneous and small genetic changes can significantly
affect outcomes.
 Future clinical trials that classify patients according to novel prognostic
factors will probably aid in creating patient-specific treatment plans with
better outcomes. 29-Mar-17
63

64. Thank You
29-Mar-1764